Conformationally constrained compounds as pharmaceutical agents

ABSTRACT

Novel substituted amino acids of formula  
                 
 
     are disclosed and are useful as agents in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. Processes for the preparation and intermediates useful in the preparation are also disclosed.

BACKGROUND OF THE INVENTION

[0001] Compounds of formula

[0002] wherein R₁ is hydrogen or a lower alkyl radical and n is 4, 5, or6 are known in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No.4,087,544. The uses disclosed are: protective effect against crampinduced by thiosemicarbazide; protective action against cardiazolecramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia,and cranial traumas; and improvement in cerebral functions. Thecompounds are useful in geriatric patients. The patents are herebyincorporated by reference.

SUMMARY OF THE INVENTION

[0003] The compounds, prodrugs, and pharmaceutically acceptable saltsare useful in a variety of disorders. The disorders include: epilepsy,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, depression, anxiety, panic, pain, and neuropathologicaldisorders.

[0004] The compounds are those of formula

[0005] or a pharmaceutically acceptable salt thereof or a prodrugthereof wherein

[0006] R₁ to R₁₀ are each independently selected from hydrogen or astraight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl;

[0007] m is an integer of from 0 to 3;

[0008] n is an integer of from 1 to 2;

[0009] o is an integer of from 0 to 3;

[0010] p is an integer of from 1 to 2;

[0011] q is an integer of from 0 to 2;

[0012] r is an integer of from 1 to 2;

[0013] s is an integer of from 1 to 3;

[0014] t is an integer of from 0 to 2; and

[0015] u is an integer of from 0 to 1.

[0016] Novel intermediates useful in the preparation of the finalcompounds are, for example:

[0017] 2-Benzyl-2-aza-spiro[4.5]decane-4,4-dicarboxylic acid dimethylester hydrochloride;

[0018] 2-Aza-spiro[4.5]decane-4,4-dicarboxylic acid dimethyl esterhydrochloride;

[0019] 1-Benzyloxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic acidtert-butyl ester;

[0020] 1-Hydroxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic acidtert-butyl ester;

[0021] 2-Aza-spiro[3.5]nonane-1,2-dicarboxylic acid 2-tert-butyl ester;

[0022][3aS-(3α7aα)]-7a-tert-Butoxycarbonylmethyl-1-oxo-octahydro-isoindole-2-carboxylicacid tert-butyl ester; and

[0023][3aS-(α7aα)]-3a-tert-Butoxycarbonylmethyl-octahydro-isoindole-2-carboxylicacid tert-butyl ester.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The compounds of the instant invention and their pharmaceuticallyacceptable salts and prodrugs are as defined by Formula I to VIII above.

[0025] Preferred compounds are those of Formula I above.

[0026] Especially preferred are those of Formula I wherein

[0027] R₁ to R₁₀ is hydrogen;

[0028] m is of from 0 to 3; and

[0029] n is 1 or 2.

[0030] More especially preferred are those compounds selected from:

[0031] (±)-2-Aza-spiro[3.5]nonane-1-carboxylic acid hydrochloride;

[0032] (±)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride;

[0033] (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride;

[0034] (S)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride; and

[0035] (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid.

[0036] Other preferred compounds are those of Formula II above.

[0037] Especially preferred are those of Formula II wherein

[0038] R₁ to R₁₀ is hydrogen,

[0039] o is from 0 to 3; and

[0040] p is 1 to 2.

[0041] Other preferred compounds are those of Formula III above wherein

[0042] R₁ to R₁₀ is hydrogen,

[0043] q is from O to 2; and

[0044] r is 1 to 2.

[0045] Especially preferred is(±)-[3aS-(3α,7aα)]-(Octahydro-isoindol-3a-yl)-acetic acidtrifluoroacetate.

[0046] Also especially preferred are compounds selected from:

[0047] 7-Methyl-2-aza-spiro[4.4]nonane-4-carboxylic acid;

[0048] [4α,5β(R*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[0049] [4α,5α(S*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[0050] [4α,5α(R*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[0051] [4α,5β(S*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[0052] 7,8-Dimethyl-2-aza-spiro[4.4]nonane-4-carboxylic acid;

[0053] 7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[0054] 7,9-Dimethyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[0055] Spiro[bicyclo[3.3.1]nonane-9,3′-pyrrolidine]-4′-carboxylic acid;

[0056]Spiro[pyrrolidine-3,2′-tricyclo[3.3.1.1^(3,7)]decane]-4-carboxylic acid;

[0057] 3-Amino-6-methyl-spiro[3.5]nonane-1-carboxylic acid;

[0058] 3-Amino-6,8-dimethyl-spiro[3.5]nonane-1-carboxylic acid;

[0059] 4-Amino-7-methyl-spiro[4.5]decane-1-carboxylic acid;

[0060] 4-Amino-7,9-dimethyl-spiro[4.5]decane-1-carboxylic acid;

[0061] 3-Amino-6-methyl-spiro[3.4]octane-1-carboxylic acid;

[0062] 3-Amino-6,7-dimethyl-spiro[3.4]octane-1-carboxylic acid;

[0063] 4-Amino-7-methyl-spiro[4.4]nonane-1-carboxylic acid; and

[0064] 4-Amino-7,8-dimethyl-spiro[4.4]nonane-1-carboxylic acid.

[0065] Pharmaceutical compositions comprising a therapeuticallyeffective amount of a compound of Formulas I-VIII above are included inthe instant invention.

[0066] Methods of using the compounds of the invention as agents fortreating epilepsy, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, depression, anxiety, panic, pain, andneuropathological disorders are part of the invention.

[0067] The term “alkyl” is a straight or branched group of from 1 to 6carbon atoms including but not limited to methyl, ethyl, propyl,n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, andn-hexyl.

[0068] Preferred groups are methyl and tert-butyl.

[0069] The benzyl and phenyl groups may be unsubstituted or substitutedby from 1 to 3 substituents selected from halogen, alkyl, alkoxy,hydroxy, carboxy, carboalkoxy, trifluoromethyl, and nitro.

[0070] Halogen includes fluorine, bromine, chlorine, and iodine.

[0071] Since amino acids are amphoteric, pharmacologically compatiblesalts when R is hydrogen can be salts of appropriate inorganic ororganic acids, for example, hydrochloric, sulphuric, phosphoric, acetic,oxalic, lactic, citric, malic, salicylic, malonic, maleic, succinic, andascorbic. Starting from corresponding hydroxides or carbonates, saltswith alkali metals or alkaline earth metals, for example, sodium,potassium, magnesium, or calcium are formed. Salts with quaternaryammonium ions can also be prepared with, for example, thetetramethyl-ammonium ion.

[0072] Prodrugs of compounds I-VIII are included in the scope of theinstant invention. Aminoacyl-glycolic and -lactic esters are known asprodrugs of amino acids (Wermuth C. G., Chemistry and Industry,1980:433-435). The carbonyl group of the amino acids can be esterifiedby known means. Prodrugs and soft drugs are known in the art (PalominoE., Drugs of the Future, 1990;15(4):361-368). The last two citations arehereby incorporated by reference.

[0073] The effectiveness of an orally administered drug is dependentupon the drug's efficient transport across the mucosal epithelium andits stability in enterohepatic circulation. Drugs that are effectiveafter parenteral administration but less effective orally, or whoseplasma half-life is considered too short, may be chemically modifiedinto a prodrug form.

[0074] A prodrug is a drug which has been chemically modified and may bebiologically inactive at its site of action, but which may be degradedor modified by one or more enzymatic or other in vivo processes to theparent bioactive form.

[0075] This chemically modified drug, or prodrug, should have adifferent pharmacokinetic profile to the parent, enabling easierabsorption across the mucosal epithelium, better salt formulation and/orsolubility, improved systemic stability (for an increase in plasmahalf-life, for example). These chemical modifications may be

[0076] 1) ester or amide derivatives which may be cleaved by, forexample, esterases or lipases. For ester derivatives, the ester isderived from the carboxylic acid moiety of the drug molecule by knownmeans. For amide derivatives, the amide may be derived from thecarboxylic acid moiety or the amine moiety of the drug molecule by knownmeans.

[0077] 2) peptides which may be recognized by specific or nonspecificproteinases. A peptide may be coupled to the drug molecule via amidebond formation with the amine or carboxylic acid moiety of the drugmolecule by known means.

[0078] 3) derivatives that accumulate at a site of action throughmembrane selection of a prodrug form or modified prodrug form,

[0079] 4) any combination of 1 to 3.

[0080] Current research in animal experiments has shown that the oralabsorption of certain drugs may be increased by the preparation of“soft” quaternary salts. The quaternary salt is termed a “soft”quaternary salt since, unlike normal quaternary salts, e.g., R—N⁺(CH₃)₃,it can release the active drug on hydrolysis.

[0081] “Soft” quaternary salts have useful physical properties comparedwith the basic drug or its salts. Water solubility may be increasedcompared with other salts, such as the hydrochloride, but more importantthere may be an increased absorption of the drug from the intestine.Increased absorption is probably due to the fact that the “soft”quaternary salt has surfactant properties and is capable of formingmicelles and unionized ion pairs with bile acids, etc., which are ableto penetrate the intestinal epithelium more effectively. The prodrug,after absorption, is rapidly hydrolyzed with release of the activeparent drug.

[0082] Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

[0083] Certain of the compounds of the present invention possess one ormore chiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof. For example,the compound of Example 1 is a mixture of all four possiblestereoisomers. The compound of Example 6 is one of the isomers. Theconfiguration of the cyclohexane ring carbon centers may be R or S inthese compounds where a configuration can be defined.

[0084] The radioligand binding assay using [³H]gabapentin and the α₂δsubunit derived from porcine brain tissue was used (Gee N. S., Brown J.P., Dissanayake V. U. K., Offord J., Thurlow R., Woodruff G. N., “TheNovel Anti-convulsant Drug, Gabapentin, Binds to the α₂δ Subunit of aCalcium Channel,” J. Biol. Chem., 1996;271:5879-5776). TABLE I IC₅₀ (μM)at Compound Structure α₂δ Binding Site (±)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride

0.35 (R)-2-Aza-spiro[4.5]decane-4- carboxylic acid hydrochloride

0.16 (S)-2-Aza-spiro[4.5]decane-4- carboxylic acid hydrochloride

>10 (±)-2-Aza-spiro[3.5]nonane-1- carboxylic acid hydrochloride

1.5 (±)-[3aS-(3α,7aα)]- (Octahydro-isoindol-3a-yl)- acetic acidtrifluoroacetate

>10 Spiro[pyrrolidine-3,2′- tricyclo[3.3.1.1^(3,7)]decane]-4- carboxylicacid

0.42 Spiro[bicyclo[3.3.1]nonane- 9,3′-pyrrolidine]-4′-carboxylic acid

0.57

[0085] Table 1 above shows the binding affinity of the compounds of theinvention to the α₂δ subunit.

[0086] The compounds of the invention are compared to Neurontin®, amarketed drug effective in the treatment of such disorders as epilepsy.Neurontin® is 1-(aminomethyl)-cyclohexaneacetic acid of structuralformula

[0087] Gabapentin (Neurontin®) is about 0.10 to 0.12 μM in this assay.The compounds of the instant invention are expected, therefore, toexhibit pharmacologic properties comparable to gabapentin. For example,as agents for convulsions, anxiety, and pain.

[0088] The present invention also relates to therapeutic use of thecompounds of the mimetic as agents for neurodegenerative disorders.

[0089] Such neurodegenerative disorders are, for example, Alzheimer'sdisease, Huntington's disease, Parkinson's disease, and AmyotrophicLateral Sclerosis.

[0090] The present invention also covers treating neurodegenerativedisorders termed acute brain injury. These include but are not limitedto: stroke, head trauma, and asphyxia.

[0091] Stroke refers to a cerebral vascular disease and may also bereferred to as a cerebral vascular incident (CVA) and includes acutethromboembolic stroke. Stroke includes both focal and global ischemia.Also, included are transient cerebral ischemic attacks and othercerebral vascular problems accompanied by cerebral ischemia. A patientundergoing carotid endarterectomy specifically or other cerebrovascularor vascular surgical procedures in general, or diagnostic vascularprocedures including cerebral angiography and the like.

[0092] Other incidents are head trauma, spinal cord trauma, or injuryfrom general anoxia, hypoxia, hypoglycemia, hypotension as well assimilar injuries seen during procedures from embole, hyperfusion, andhypoxia.

[0093] The instant invention would be useful in a range of incidents,for example, during cardiac bypass surgery, in incidents of intracranialhemorrhage, in perinatal asphyxia, in cardiac arrest, and statusepilepticus.

[0094] Pain refers to acute as well as chronic pain.

[0095] Acute pain is usually short-lived and is associated withhyperactivity of the sympathetic nervous system. Examples arepostoperative pain and allodynia.

[0096] Chronic pain is usually defined as pain persisting from 3 to 6months and includes somatogenic pains and psychogenic pains. Other painis nociceptive.

[0097] Still other pain is caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Neuropathic pain includes, but is not limited to paincaused by nerve injury such as, for example, the pain diabetics sufferfrom.

[0098] Psychogenic pain is that which occurs without an organic originsuch as low back pain, atypical facial pain, and chronic headache.

[0099] Other types of pain are: inflammatory pain, osteoarthritic pain,trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legsyndrome, acute herpetic and postherpetic neuralgia, causalgia, brachialplexus avulsion, occipital neuralgia, gout, phantom limb, burn, andother forms of neuralgia, neuropathic and idiopathic pain syndrome.

[0100] A skilled physician will be able to determine the appropriatesituation in which subjects are susceptible to or at risk of, forexample, stroke as well as suffering from stroke for administration bymethods of the present invention.

[0101] The compounds of the invention are also expected to be useful inthe treatment of depression. Depression can be the result of organicdisease, secondary to stress associated with personal loss, oridiopathic in origin. There is a strong tendency for familial occurrenceof some forms of depression suggesting a mechanistic cause for at leastsome forms of depression. The diagnosis of depression is made primarilyby quantification of alterations in patients mood. These evaluations ofmood are generally performed by a physician or quantified by aneuropsychologist using validated rating scales, such as the HamiltonDepression Rating Scale or the Brief Psychiatric Rating Scale. Numerousother scales have been developed to quantify and measure the degree ofmood alterations in patients with depression, such as insomnia,difficulty with concentration, lack of energy, feelings ofworthlessness, and guilt. The standards for diagnosis of depression aswell as all psychiatric diagnoses are collected in the Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition) referred to asthe DSM-IV-R manual published by the American Psychiatric Association,1994.

[0102] GABA is an inhibitory neurotransmitter with the central nervoussystem. Within the general context of inhibition, it seems likely thatGABA-mimetics might decrease or inhibit cerebral function and mighttherefore slow function and decrease mood leading to depression.

[0103] The compounds of the instant invention may produce ananticonvulsant effect through the increase of newly created GABA at thesynaptic junction. If gabapentin does indeed increase GABA levels or theeffectiveness of GABA at the synaptic junction, then it could beclassified as a GABA-mimetic and might decrease or inhibit cerebralfunction and might, therefore, slow function and decrease mood leadingto depression.

[0104] The fact that a GABA agonist or GABA-mimetic might work just theopposite way by increasing mood and thus, be an antidepressant, is a newconcept, different from the prevailing opinion of GABA activityheretofore.

[0105] The compounds of the instant invention are also expected to beuseful in the treatment of anxiety and of panic as demonstrated by meansof standard pharmacological procedures.

MATERIAL AND METHODS

[0106] Carrageenin-Induced Hyperalgesia

[0107] Nociceptive pressure thresholds were measured in the rat pawpressure test using an analgesimeter (Randall-Selitto method: Randall L.O. and Selitto J. J., “A method for measurement of analgesic activity oninflamed tissue,” Arch. Int. Pharmacodyn., 1957;4:409-419). MaleSprague-Dawley rats (70-90 g) were trained on this apparatus before thetest day. Pressure was gradually applied to the hind paw of each rat andnociceptive thresholds were determined as the pressure (g) required toelicit paw withdrawal. A cutoff point of 250 g was used to prevent anytissue damage to the paw. On the test day, two to three baselinemeasurements were taken before animals were administered 100 μL of 2%carrageenin by intraplantar injection into the right hind paw.Nociceptive thresholds were taken again 3 hours after carrageenin toestablish that animals were exhibiting hyperalgesia. Animals were dosedwith either gabapentin (3-300 mg, s.c.), morphine (3 mg/kg, s.c.) orsaline at 3.5 hours after carrageenin and nociceptive thresholds wereexamined at 4, 4.5, and 5 hours postcarrageenin.

[0108] (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride wastested in the above carrageenan-induced hyperalgesia model. The compoundwas dosed orally at 30 mg/kg, and 1 hour postdose gave a percent ofmaximum possible effect (MPE) of 53%. At 2 hours postdose, it gave only4.6% of MPE.

[0109] Semicarbazide-Induced Tonic Seizures

[0110] Tonic seizures in mice are induced by subcutaneous administrationof semicarbazide (750 mg/kg). The latency to the tonic extension offorepaws is noted. Any mice not convulsing within 2 hours aftersemicarbazide are considered protected and given a maximum latency scoreof 120 minutes.

[0111] Animals

[0112] Male Hooded Lister rats (200-250 g) are obtained from Interfauna(Huntingdon, UK) and male TO mice (20-25 g) are obtained from Bantin andKingman (Hull, UK). Both rodent species are housed in groups of six. TenCommon Marmosets (Callithrix Jacchus) weighing between 280 and 360 g,bred at Manchester University Medical School (Manchester, UK) are housedin pairs. All animals are housed under a 12-hour light/dark cycle(lights on at 07.00 hour) and with food and water ad libitum.

[0113] Drug Administration

[0114] Drugs are administered either intraperitoneally (IP) orsubcutaneously (SC) 40 minutes before the test in a volume of 1 mL/kgfor rats and marmosets and 10 mL/kg for mice.

[0115] Mouse Light/Dark Box

[0116] The apparatus is an open-topped box, 45 cm long, 27 cm wide, and27 cm high, divided into a small (⅖) and a large (⅗) area by a partitionthat extended 20 cm above the walls (Costall B., et al., “Exploration ofmice in a black and white box: validation as a model of anxiety,”Pharmacol. Biochem. Behav., 1989;32:777-785).

[0117] There is a 7.5×7.5 cm opening in the center of the partition atfloor level. The small compartment is painted black and the largecompartment white. The white compartment is illuminated by a 60-Wtungsten bulb. The laboratory is illuminated by red light. Each mouse istested by placing it in the center of the white area and allowing it toexplore the novel environment for 5 minutes. The time spent in theilluminated side is measured (Kilfoil T., et al., “Effects of anxiolyticand anxiogenic drugs on exploratory activity in a simple model ofanxiety in mice,” Neuropharmacol., 1989;28:901-905).

[0118] Rat Elevated X-Maze

[0119] A standard elevated X-maze (Handley S. L., et al., “Effects ofalpha-adrenoceptor agonists and antagonists in a maze-exploration modelof ‘fear’-motivated behavior,” Naunyn-Schiedeberg's Arch. Pharmacol., 1984;327: 1-5), was automated as previously described (Field, et al.,“Automation of the rat elevated X-maze test of anxiety,” Br. J.Pharmacol., 1991; 102(Suppl.):304P). The animals are placed on thecenter of the X-maze facing one of the open arms. For determininganxiolytic effects the entries and time spent on the end half sectionsof the open arms is measured during the 5-minute test period (Costall,et al., “Use of the elevated plus maze to assess anxiolytic potential inthe rat,” Br. J. Pharmacol., 1989;96(Suppl.):312p).

[0120] Marmoset Human Threat Test

[0121] The total number of body postures exhibited by the animal towardsthe threat stimulus (a human standing approximately 0.5 m away from themarmoset cage and staring into the eyes of the marmoset) is recordedduring the 2-minute test period. The body postures scored are slitstares, tail postures, scent marking of the cage/perches, piloerection,retreats, and arching of the back. Each animal is exposed to the threatstimulus twice on the test day before and after drug treatment. Thedifference between the two scores is analyzed using one-way analysis ofvariance followed by Dunnett's t-test. All drug treatments are carriedout SC at least 2 hours after the first (control) threat. Thepretreatment time for each compound is 40 minutes.

[0122] Rat Conflict Test

[0123] Rats are trained to press levers for food reward in operantchambers. The schedule consists of alternations of four 4-minuteunpunished periods on variable interval of 30 seconds signaled bychamber lights on and three 3-minute punished periods on fixed ratio 5(by footshock concomitant to food delivery) signaled by chamber lightsoff. The degree of footshock is adjusted for each rat to obtainapproximately 80% to 90% suppression of responding in comparison withunpunished responding. Rats receive saline vehicle on training days.

[0124] DBA2 Mouse Model of Anticonvulsant Efficacy

[0125] All procedures were carried out in compliance with the NIH Guidefor the Care and Use of Laboratory Animals under a protocol approved bythe Parke-Davis Animal Use Committee. Male DBA/2 mice, 3 to 4 weeks oldwere obtained from Jackson Laboratories, Bar Harbour, Me. Immediatelybefore anticonvulsant testing, mice were placed upon a wire mesh, 4inches square, suspended from a steel rod. The square was slowlyinverted through 180° and mice observed for 30 seconds. Any mousefalling from the wire mesh was scored as ataxic (Coughenour L. L.,McLean J. R., Parker R. B., “A new device for the rapid measurement ofimpaired motor function in mice,” Pharm. Biochem. Behav.,1977;6(3):351-3). Mice were placed into an enclosed acrylic plasticchamber (21 cm height, approximately 30 cm diameter) with ahigh-frequency speaker (4 cm diameter) in the center of the top lid. Anaudio signal generator (Protek model B-810) was used to produce acontinuous sinusoidal tone that was swept linearly in frequency between8 kHz and 16 kHz once each 10 msec. The average sound pressure level(SPL) during stimulation was approximately 100 dB at the floor of thechamber. Mice were placed within the chamber and allowed to acclimatizefor one minute. DBA/2 mice in the vehicle-treated group responded to thesound stimulus (applied until tonic extension occurred, or for a maximumof 60 sec) with a characteristic seizure sequence consisting of wildrunning followed by clonic seizures, and later by tonic extension, andfinally by respiratory arrest and death in 80% or more of the mice. Invehicle-treated mice, the entire sequence of seizures to respiratoryarrest lasts approximately 15 to 20 seconds. The incidence of all theseizure phases in the drug-treated and vehicle-treated mice wasrecorded, and the occurrence of tonic seizures were used for calculatinganticonvulsant ED₅₀ values by probit analysis (Litchfield J. T.,Wilcoxon F. “A simplified method for evaluating dose-effectexperiments,” J. Pharmacol., 1949;96:99-113). Mice were used only oncefor testing at each dose point. Groups of DBA/2 mice (n=5-10 per dose)were tested for sound-induced seizure responses 2 hours (previouslydetermined time of peak effect) after given drug orally. All drugs inthe present study were dissolved in distilled water and given by oralgavage in a volume of 10 mL/kg of body weight. Compounds that areinsoluble will be suspended in 1% carboxymethocellulose. Doses areexpressed as weight of the active drug moiety.

[0126] The compounds of the instant invention are also expected to beuseful in the treatment of pain and phobic disorders (Am. J. PainManag., 1995;5:7-9).

[0127] The compounds of the instant invention are also expected to beuseful in treating the symptoms of manic, acute or chronic, singleupside, or recurring depression. They are also expected to be useful intreating and/or preventing bipolar disorder (U.S. Pat. No. 5,510,381).

[0128] The compounds of the present invention can be prepared andadministered in a wide variety of oral and parenteral dosage forms.Thus, the compounds of the present invention can be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

[0129] For preparing pharmaceutical compositions from the compounds ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

[0130] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component.

[0131] In tablets, the active component is mixed with the carrier havingthe necessary binding properties in suitable proportions and compactedin the shape and size desired.

[0132] The powders and tablets preferably contain from five or ten toabout seventy percent of the active compound. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

[0133] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

[0134] Liquid form preparations include solutions, suspensions, andemulsions, for example, water or water propylene glycol solutions. Forparenteral injection liquid preparations can be formulated in solutionin aqueous polyethylene glycol solution.

[0135] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizing and thickening agents as desired.

[0136] Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

[0137] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0138] The pharmaceutical preparation is preferably in unit dosage form.In such form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsules, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0139] The quantity of active component in a unit dose preparation maybe varied or adjusted from 0.1 mg to 1 g according to the particularapplication and the potency of the active component. In medical use thedrug may be administered three times daily as, for example, capsules of100 or 300 mg. The composition can, if desired, also contain othercompatible therapeutic agents.

[0140] In therapeutic use, the compounds utilized in the pharmaceuticalmethod of this invention are administered at the initial dosage of about0.01 mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg toabout 100 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

[0141] The following examples are illustrative of the instant invention;they are not intended to limit the scope.

EXAMPLE 1

[0142]

[0143] Reagents:

[0144] (i) TiCl₄, MeO₂CCH₂CO₂Me, pyridine, tetrahydrofuran;

[0145] (ii) N-Benzylglycine hydrochloride, Et₃N, paraformaldehyde, PhH;

[0146] (iii) Pearlman's catalyst, methanol, H₂;

[0147] (iv) 6N HCl.

[0148] 2-Cyclohexylidene-malonic acid dimethyl ester (2)

[0149] To 20 mL of tetrahydrofuran cooled at −78° C. was slowly added,under an argon atmosphere, TiCl₄ (1 M in CH₂Cl₂; 100 mL; 100 mmol).After the addition was complete, the reaction mixture was warmed up to−10° C. To the mixture was then successively added dimethylmalonate(6.73 g; 51 mmol), cyclohexanone 1 (5 g; 51 mmol) over 5 minutes andpyridine (16.4 mL; 201 mmol) over 1 hour 30 minutes. The brownsuspension was then allowed to warm up to room temperature, stirredovernight and diluted with water (50 mL). The phases were separated, andthe organic phase was washed with water, dried over MgSO₄, and thesolvent removed in vacuo. The crude oil was chromatographed over silicagel (ether/heptane 1:1) to give 2 as a pale yellow solid (6.35 g; 30mmol; 58%).

[0150]¹H NMR (CDCl₃) δ ppm: 1.6 (m, 6H); 2.5 (m, 4H); 3.75 (s, 6H).

[0151] MS ES+ [MW+1]⁺: 213.

[0152]2-Benzyl-2-aza-spiro[4.5]decane-4,4-dicarboxylic acid dimethylester hydrochloride (3)

[0153] A solution of dimethyl (cyclohexylidene) malonate 2 (594 mg; 2.8mmol), N-benzylglycine hydrochloride (1.41 g; 6.99 mmol), triethylamine(0.97 mL; 6.95 mmol), and paraformaldehyde (671 mg; 22.36 mmol) inbenzene (18 mL) was slowly heated up to 125° C. (oil bath) (Dean-Stark).After stirring for 2 hours, the reaction mixture was cooled to roomtemperature, diluted with toluene (20 mL), and washed with brine. Theaqueous phase was extracted with toluene (2×10 mL). The organic phaseswere combined, dried over MgSO₄, and evaporated to give a brown oilwhich was purified on silica gel chromatography (EtOAc/heptane 1:3). Theresulting pale yellow oil was diluted in diethyl ether (10 mL), and thecompound was extracted with 2N HCl (2×5 mL). The aqueous phases werecombined, washed with diethyl ether, and concentrated in vacuo to give 3as a white solid (238 mg; 0.62 mmol; 22%).

[0154]¹H NMR (D₂O) δ ppm: 1.2 to 1.9 (m, 10H); 3.65 and 3.9 ([AB]q, 2H);3.9 (d, 6H); 4.1 and 4.25 ([AB]q, 2H); 4.65 (s, 2H); 7.6 (m, 5H).

[0155] MS ES⁺ [MW+1]⁺: 346.

[0156] 2-Aza-spiro[4.5]decane-4,4-dicarboxylic acid dimethyl esterhydrochloride (4)

[0157] A solution of 3 (238 mg; 0.62 mmol) and 10% Palladium hydroxideon carbon (47 mg; 20% w/w) in methanol (10 mL) was stirred overnight at40° C. under a hydrogen atmosphere (55 psi). The catalyst was filteredoff through a celite pad, and the filtrate was evaporated under vacuumto give 4 as a yellow solid (170 mg; 0.58 mmol; 93%).

[0158]¹H NMR (D₂O) δ ppm: 1.2 to 1.8 (m, 10H); 3.65 (s, 2H); 3.9 (s,6H); 4.01 (s, 2H).

[0159] MS ES+ [MW+1]⁺: 256.

[0160] 2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride (5)

[0161] A solution of 4 (170 mg; 0.58 mmol) in 6N HCl (5 mL) was stirredovernight at 145° C. After cooling, the solvent was removed under vacuumto yield 5 as a pale yellow solid (153 mg; 0.58 mmol; quant.).

[0162]¹H NMR (D₂O) δ ppm: 1.39 to 1.8 (m, 10H); 3.1 (t, 1H); 3.4 ([AB]q,2H); 3.7 (d[AB]q, 2H).

[0163] MS ES+ [MW+1]⁺: 184.

[0164] C, H, N Calc. for C₁₀H₁₇NO₂.1.75HCl.1.0H₂O: C, 45.31; H, 7.89; N,5.28.

[0165] Observed: C, 45.65; H, 7.69; N, 5.62.

EXAMPLE 1A

[0166]

[0167] Reagents:

[0168] (i) HCl.BnNHCH₂CO₂H, Et₃N, HCHO, PhH, reflux (82%);

[0169] (ii) 6N HCl reflux (94%);

[0170] (iii) MeOH, HCl, reflux (65%);

[0171] (iv) Pd(OH)₂/C, H₂, MeOH (97%);

[0172] (v) BnOCOCl, Py, CH₂Cl₂, (88%);

[0173] (vi) Dioxane/Aq NaOH (89%);

[0174] (vii) CH₂Cl₂, (COCl)₂, HCONMe₂ then(R)-(+)-1-(2-Napthyl)ethylamine followed by flash chromatography(20a)—43% and (20b)—39%;

[0175] (viii) 6N HCl, THF reflux (73%);

[0176] (ix) 6N HCl, THF reflux (78%).

[0177] 2-Benzyl-2-aza-spiro[4.5]decane-4-carboxylic acid methyl ester(4)

[0178] A solution of (1) (4 g; 20.70 mmol), N-benzylglycinehydrochloride (10.4 g; 51.57 mmol), triethylamine (7.2 mL; 51.65 mmol),and paraformaldehyde (5.2 g; 173.30 mmol) in benzene (120 mL) wasrefluxed for 2 hours using a Dean-Stark apparatus. After cooling, thereaction mixture was diluted with toluene (200 mL) and washed withbrine. The aqueous phase was extracted with toluene (3×30 mL). Theorganic extracts were combined, dried over MgSO₄, and concentrated invacuo. The crude oil was purified over silica-gel chromatography inEtOAc/heptane (1:3) to give a yellow oil which was diluted in ether (30mL) and extracted with 3N HCl (3×25 mL). The aqueous phase was washedwith ether (2×30 mL) and was concentrated under vacuum to give (2) as awhite powder (6.20 g; 17.08 mmol) which was used without any furtherpurification. A solution of (2) (6.2 g; 17.08 mmol) in 6N HCl (120 mL)was refluxed overnight. Evaporating the solvent in vacuo gave 5 g (16.13mmol; 77% from (1)) of (3) as a pale yellow solid which was immediatelyesterified. Acetyl chloride (5 mL; 70.32 mmol) was slowly added tomethanol (100 mL), at 0° C., under an argon atmosphere. After stirringfor 10 minutes, this solution was transferred to a flask containing (3)(5 g; 16.13 mmol), under an argon atmosphere. The reaction mixture wasthen stirred at 95° C. for 3 hours. After cooling, the methanol wasremoved in vacuo. The residue was basified with saturated aqueousNa₂CO₃, and was extracted with ether (3×30 mL). The organic phases werecombined, dried over MgSO₄, and concentrated to give 3 g (10.44 mmol;50% from (1)) of (4) as a pale yellow liquid.

[0179]¹H NMR (CDCl₃) 400 MHz δ: 1.0 to 1.7 (m, 10H); 2.25 (d, 1H); 2.65to 2.9 (m, 4H); 3.6 ([AB]q, 2H); 3.65 (s, 3H, OCH₃)); 7.3 (m, 5H, Ph).

[0180] MS (ES⁺) m/e: 288 ([MH]⁺, 100%).

[0181] 2-Aza-spiro[4.5]decane-2,4-dicarboxylic acid 2-benzyl ester4-methyl ester (6)

[0182] A solution of (4) (3 g; 10.44 mmol) and 10% Pd (OH)₂/C (0.60 g;20% w/w) in methanol (50 mL) was stirred for 24 hours at 40° C. under atatmosphere of dry hydrogen gas. The catalyst was filtered off through acelite pad, and the filtrate was concentrated in vacuo to give 2 g(10.14 mmol; 97%) of (5) as a colorless oil which was used without anyfurther purification. To a solution of (5) (2 g; 10.14 mmol) in drydichloromethane (100 mL) was successively added, at 0° C., under anargon atmosphere, pyridine (2.04 mL; 25.35 mmol), andbenzylchloroformate (2.89 mL; 20.24 mmol). The reaction mixture was thenallowed to stir at room temperature for 2 days. The reaction mixture waswashed (2×50 mL) with 1N HCl, dried over MgSO₄, and concentrated invacuo. The crude oil was purified by silica-gel flash chromatography inether/heptane (1:1) to give 2.97 g (8.96 mmol; 88%) of (6) as acolorless oil.

[0183]¹H NMR (CDCl₃) 400 MHz δ: 1.15 to 1.7 (m, 10H); 2.8 (m, 1H); 3.3(m, 1H); 3.45 to 3.8 (m, 6H); 5.15 ([AB]q, 2H, PhCH₂); 7.3 (m, 5H, Ph).

[0184] MS (ES⁺) m/e: 332 ([MH]⁺, 100%).

[0185] 2-Aza-spiro[4.5]decane-2,4-dicarboxylic acid 2-benzyl ester (7)

[0186] To a solution of (6) (300 mg; 0.9 mmol) in a mixturedioxane/water (6 mL; 9:1) was added a 2 M solution of NaOH (0.90 mL; 1.8mmol). The reaction mixture was stirred at 35° C. for 6 hours. Solventswere removed in vacuo. The residue was diluted in water (15 mL) and waswashed with diethyl ether (3×10 mL). The aqueous phase was acidifiedwith 2N HCl and was extracted with ethyl acetate (3×15 mL). The ethylacetate extracts were combined, dried over MgSO₄, and concentrated togive 254 mg (0.8 mmol; 89%) of (7) as a colorless gum.

[0187]¹H NMR (CDCl₃) 400 MHz δ: 1.2 to 1.75 (m, 10H); 2.8 (m, 1H); 3.3(m, 1H); 3.5 to 3.8 (m, 3H); 5.1 (ABq, 2H); 7.3 (m, 5H).

[0188] MS (ES⁺) m/e: 318 ([MH]⁺, 100%).

[0189](4S,1′R)-4-(1′-Naphthalen-2-yl-ethylcarbamoyl)-2-aza-spiro[4.5]decane-2-carboxylicacid benzyl ester (8a) and

[0190](4R,1′R)-4-(1′-Naphthalen-2-yl-ethylcarbamoyl)-2-aza-spiro[4.5]decane-2-carboxylicacid benzyl ester (8b)

[0191] To a cooled (0° C.) solution of (7) (1.71 g; 5.38 mmol) in drydichloromethane (35 mL) were successively added, under an argonatmosphere, oxalyl chloride (0.56 mL; 6.42 mmol) and dimethylformamide(20 μL; 0.26 mmol). The reaction mixture was stirred at 0° C. for 30minutes and then was allowed to stir at room temperature for 2 hours.The solvent was removed in vacuo, and the residue was diluted in drydichloromethane (35 mL). This solution was then added to a solution of(R)-(+)-1-(2-naphthyl)ethylamine (1.10 g; 6.42 mmol) and triethylamine(0.90 mL; 6.42 mmol) in dry dichloromethane (50 mL) under an argonatmosphere. The reaction mixture was stirred at room temperatureovernight. 2N HCl (30 mL) was added, and the organic and aqueous phaseswere separated. The organic phase was washed with water (30 mL), driedover MgSO₄, and concentrated to give a pale yellow oil which waspurified over silica-gel chromatography in EtOAc/heptane (1:1) to give1.1 g (2.34 mmol; 43%) of (8a) and 1.0 g (2.12 mmol; 39%) of (8b) aswhite solids.

[0192]¹H NMR (CDCl₃) 400 MHz δ: (8a): 1.2 to 1.65 (m, 13H); 2.4 (m, 1H);3.35 (d, H); 3.5 to 3.8 (m, 3H); 5.1 (m, 2H); 5.3 (m, 1H); 5.7 (t, 1H);7.3 to 7.8 (m, 12H). (8b): 1.2 to 1.65 (m, 13H); 2.4 (m, 1H); 3.25 (d,1H); 3.5 to 3.8 (m, 3H); 5.1 (m, 2H); 5.3 (m, 1H); 5.7 (t, 1H); 7.3 to7.8 (m, 12H).

[0193] MS (ES⁺) m/e: (8a): 471 ([MH]⁺, 100%); (8b): 471 ([MH]⁺, 100%).

[0194] (S)-2-Aza-spiro[4.5]decane-4-carboxylic acid (9a)

[0195] To a solution of (8a) (770 mg; 1.64 mmol) in THF (5 mL) was added6N aqueous HCl (40 mL). The reaction mixture was stirred under refluxovernight. After cooling, the reaction mixture was washed with EtOAc(2×20 mL). The phases were separated, and the aqueous phase wasconcentrated to dryness under vacuum. The crude residue was dissolved in6N aqueous HCl (40 mL), and the reaction mixture was stirred underreflux for 60 hours. After cooling, the reaction mixture was washed withEtOAc (2×20 mL). The phases were separated, and the aqueous phase wasconcentrated to dryness to leave a solid which was dissolved in water.Removing water under vacuum led to (9a) as a white powder (263 mg; 1.20mmol; 73%).

[0196]¹H NMR (CDCl₃) 400 MHz δ: 1.2 to 1.8 (m, 10H); 3.1 (t, 1H); 3.4([AB]q, 2H); 3.7 (m, 2H).

[0197] MS (ES⁺) m/e: 184 ([MH]⁺, 100%).

[0198] (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid (9b)

[0199] (8b) (553 mg; 1.17 mmol) was converted to 200 mg (0.91 mmol; 78%)of (12b) by the same procedure for (9a) to (12a).

[0200]¹H NMR (CDCl₃) 400 MHz δ: 1.2 to 1.8 (m, 10H); 3.1 (t, 1H); 3.4([AB]q, 2H); 3.7 (m, 2H).

[0201] MS (ES⁺) m/e: 184 ([MH]⁺, 100%).

EXAMPLE 2

[0202]

[0203] Reagents:

[0204] (i) BnOCH₂CHO, LiN(iPr)₂, THF, −78° C. to −20° C.,

[0205] (ii) AlCl₃, LiAILi₄, Et₂O;

[0206] (iii) BOC₂O, dichloromethane;

[0207] (iv) MeSO₂Cl, Et₃N, dichloromethane;

[0208] (v) NaH, dimethylformamide;

[0209] (vi) Ammonium formate, 10% Pd/C, MeOH;

[0210] (vii) NaIO₄, RuCl₃, CCl₄, CH₃CN, H₂O;

[0211] (viii) 1N HCl (g) in ethyl acetate.

[0212] 1-(2-Benzyloxy-1-hydroxy-ethyl)-cyclohexanecarbonitrile (2)

[0213] Lithium diisopropylamide was prepared by dropwise addition ofn-BuLi (2.03 mL; 2.5 M in Hexanes; 5.08 mmol) to a stirred and cooled(−10° C.) solution of i-Pr₂NH (0.84 mL; 6.0 mmol) in dry tetrahydrofuran(40 mL). Stirring was continued for 20 minutes. The mixture was cooledto −78° C. and cyclohexane carbonitrile 1 (500 mg; 4.62 mmol) was addedover 5 minutes. After a further 30 minutes, benzyloxyacetaldehyde (0.97mL; 6.93 mmol) was added dropwise. Stirring was continued at −78° C. for7 hours. The reaction mixture was then allowed to stir overnight at −20°C. Saturated aqueous NH₄Cl was added (10 mL), and the mixture wasextracted with diethyl ether (2×20° mL), dried over MgSO₄ andevaporated. The residue was purified over silica gel chromatography(ether/heptane 1:1) to give 2 as a white solid (872 mg; 3.37 mmol; 73%)

[0214]¹H NMR (CDCl₃) δ ppm: 1.1 to 1.8 (m, 9H); 2.2 (d, 1H); 2.75 (s,1H); 3.6 to 3.8 (m, 3H); 4.6 ([AB]q, 2H); 7.4 (m, 5H).

[0215] MS ES+ [MW+1]⁺: 259.

[0216] 1-(1-Aminomethyl-cyclohexyl)-2-benzyloxy-ethanol (3)

[0217] To AlCl₃ (410 mg; 3.07 mmol) was added, at −78° C. and under anargon atmosphere, 3 mL of diethyl ether. The dry ice-bath was removed.The mixture was stirred at room temperature for 10 minutes, and then wasadded to LiAlH₄ (3.02 mL; 1 M in diethyl ether; 3.02 mmol). A solutionof 2 (300 mg; 1.16 mmol) in diethyl ether (3 mL) was then added over thecourse of 2 minutes, and the reaction mixture was stirred overnight atroom temperature. The mixture was quenched by cautious addition of water(2 mL) followed by addition of 10% H₂SO₄ (30 mL). The aqueous phase waswashed with diethyl ether (3×15 mL), basified with NaOH pellets (excess)and extracted with diethyl ether (3×15 mL). The organic phases werecombined, washed with brine, dried over MgSO₄, and evaporated to give 3as a colorless oil (230 mg; 0.87 mmol; 76%) which was used withoutfurther purification.

[0218]¹H NMR (CDCl₃) δ ppm: 1.2 to 1.7 (m, 10H); 2.75 (d, 11H); 2.95 (s,1H); 3.6 (dd, 1H); 3.7 (dd, 1H); 4.6 ([AB]q, 2H); 7.3 (m, 5H).

[0219] MS ES+ [MW+1]⁺: 264.

[0220] [1-(2-Benzyloxy-1-hydroxy-ethyl)-cyclohexylmethyl]-carbamic acidtert-butyl ester (4)

[0221] A solution of 3 (244 mg; 0.92 mmol) and BOC₂O (242 mg; 1.11 mmol)in CH₂Cl₂ (8 mL) was stirred at room temperature for 24 hours under anargon atmosphere. The solvent was removed under vacuum, and the crudeoil was purified over silica gel chromatography (ether/heptane 1:1) togive 4 as a colorless oil (298 mg; 0.82 mmol; 89%).

[0222]¹H NMR (CDCl₃) δ ppm: 1.1 to 1.6 (m, 10H); 1.4 (s, 9H); 2.8 (s,1H); 3.1 (dd, 1H); 3.35 (dd, 1H); 3.5 (t, 1H); 3.65 (dd, 1H); 3.75 (dd,1H); 4.6 ([AB]q, 2H); 5.5 (bs, 1H); 7.3 (m, 5H).

[0223] MS ES⁺ [MW+1]⁺: 364.

[0224] Methanesulfonic acid2-benzyloxy-1-[1-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-ethylester (5)

[0225] To a cooled (−10° C.) solution of 4 (290 mg; 0.79 mmol) andtriethylamine (0.33 mL; 2.39 mmol) in CH₂Cl₂ (5 mL) was added, under anargon atmosphere, MsCl (0.154 mL; 1.93 mmol) diluted in CH₂Cl₂ (0.5 mL).The reaction mixture was then allowed to stir at room temperature for 2days. The solvent was removed under vacuum, and the residue was dilutedin diethyl ether, washed with water, dried over MgSO₄, and concentrated.The crude oil was purified over silica gel chromatography (ether/heptane1:1) to give 5 as a colorless oil (200 mg; 0.45 mmol; 57%).

[0226]¹H NMR (CDCl₃) δ ppm: 1.2 to 1.6 (m, 10H); 1.2 (s, 9H); 3 (s, 1H);3.05 (dd, 1H); 3.25 (dd, 1H); 3.8 (m, 2H); 4.55 ([AB]q, 2H); 4.75 (m,1H); 5.05 (m, 1H); 7.3 (m, 5H).

[0227] MS ES+ [MW+1]⁺: 442

[0228] 1-Benzyloxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic acidtert-butyl ester (6)

[0229] A solution of 5 (2.53 g; 5.73 mmol) and NaH (460 mg; 60% w/w inoil; 11.47 mmol) in dry DMF (115 mL) was stirred at 45° C. for 1 hourunder an argon atmosphere. The reaction was quenched by cautiousaddition of saturated NH₄Cl (200 mL), and the aqueous phase wasextracted with diethyl ether (2×100 mL). The organic phases werecombined, dried over MgSO₄, and evaporated. The residue was purifiedover silica gel chromatography (ether/heptane 1:2) to give 6 as acolorless oil (1.20 g; 3.48 mmol; 59%).

[0230]¹H NMR (CDCl₃) δ ppm: 1.2 to 1.8 (m, 10H); 1.4 (s, 9H); 3.45([AB]q, 2H); 3.7 (m, 2H); 3.85 (m, 1H); 4.55 ([AB]q, 2H); 7.3 (m, 5H).

[0231] MS ES+ [MW+1]⁺: 346.

[0232] 1-Hydroxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic acidtert-butyl ester (7)

[0233] A solution of 6 (349 mg; 1.01 mmol), ammonium formate (638 mg;10.1 mmol) and 10% Pd/C (349 mg; 1 eq. w/w) in methanol (20 mL) washeated to reflux for 2 hours. Ammonium formate (638 mg; 10.1 mmol) and10% Pd/C (175 mg; 0.5 eq. w/w) were added, and the reaction mixture wasrefluxed for a further 2 hours. After cooling, the catalyst was filteredoff through a celite pad, and the filtrate was evaporated. The crude oilwas purified over silica gel chromatography (ether/heptane 4:1) to give7 as a white solid (193 mg; 0.76 mmol; 75%).

[0234]¹H NMR (CDCl₃) δ ppm: 1.1 to 1.8 (m, 10H); 1.45 (s, 9H); 3.55([AB]q, 2H); 3.7 (m, 1H); 3.9 (m, 2H); 4.45 (bs, 1H).

[0235] MS ES+ [MW+1]⁺: 256.

[0236] C, H, N Calc.: C, 65.85; H, 9.87; N, 5.48. Observed: C, 65.54; H,9.65; N, 5.39.

[0237] 2-Aza-spiro[3.5]nonane-1,2-dicarboxylic acid 2-tert-butyl ester(8)

[0238] To 7 (212 mg; 0.83 mmol) dissolved in a mixture of CCl₄ (1.7 mL),CH₃CN (1.7 mL), and water (2.5 mL) was added NaIO₄ (710 mg; 3.32 mmol).After 15 minutes, hydrated RuCl₃ (4.8 mg; 2.2% mol) was added, and thereaction mixture was stirred at room temperature for 2 hours. Themixture was then extracted with CH₂Cl₂ (3×5 mL), washed with water,dried over MgSO₄ and concentrated. The crude oil was diluted in diethylether (5 mL) and saturated aqueous Na₂CO₃ (5 mL) was added. The aqueousphase was washed with diethyl ether (3×5 mL), acidified up to pH=3 with1N HCl and extracted with diethyl ether (3×5 mL). The organic phaseswere combined, washed with water and concentrated in vacuo to give 8 asa white solid (185 mg; 0.69 mmol; 83%).

[0239]¹H NMR (CDCl₃) δ ppm: 1.2 to 1:8 (m, 10H); 1.5 (s, 9H); 3.6([AB]q, 2H); 4.3 (s, 1H).

[0240] MS ES+ [MW+1]⁺: 270.

[0241] C, H, N Calc.: C, 62.43; H, 8.60; N, 5.20. Observed: C, 62.40; H,8.75; N, 5.01.

[0242] 2-Aza-spiro[3.5]nonane-1-carboxylic acid hydrochloride (9)

[0243] Compound 8 (21.5 mg; 0.079 mmol) was dissolved in a dry 1 MHCl(g) solution in ethyl acetate (0.4 mL; 0.4 mmol) under an argonatmosphere. The reaction mixture was stirred at room temperature for 5hours. The white precipitate was collected by filtration and washedseveral times with dry diethyl ether (2 mL) and dried under vacuum togive 9 as a white powder (15.2 mg; 0.074 mmol; 92%).

[0244]¹H NMR (CDCl₃) δ ppm: 1.03 to 1.84 (m, 10H); 3.7 ([AB]q, 2H); 4.4(s, 1H).

[0245] MS ES+ [MW+1]⁺: 170.

[0246] MP: 163-165° C.

[0247] C, H, N Calc. C₉H₁₅NO₂.1.0HCl: C, 52.55; H, 7.84; N, 6.81.Observed: C, 52.50; H, 7.74; N, 6.88.

EXAMPLE 3

[0248]

[0249] Reagents:

[0250] (i) MeNO₂, (Bu)₄N⁺F⁻; tetrahydrofuran;

[0251] (ii) Ni sponge, H₂, MeOH;

[0252] (iii) (BOC)₂O, 4-dimethylamino pyridine, Et₃N, tetrahydrofuran;

[0253] (iv) LiN(iPr)₂, Me₃CO₂CCH₂Br, tetrahydrofuran;

[0254] (v) LiBHEt₃, tetrahydrofuran then Et₃SiH, BF₃.Et₂O,dichloromethane;

[0255] (iv) CF₃CO₂H, dichloromethane.

[0256] 2-Nitromethyl-cyclohexanecarboxylic acid methyl ester (2)

[0257] A solution of cyclohex-1-enecarboxylic acid methyl ester 1 (5.15g; 36.7 mmol), tetrabutyl ammonium fluoride (55.10 mL; 1 M in THF; 55.1mmol) and nitromethane (3.97 mL; 73.5 mmol) in tetrahydrofuran (60 mL)was heated to reflux for 4 hours. After cooling to room temperature, thereaction mixture was diluted with diethyl ether (500 mL), washed with 2NHCl (2×100 mL) and then with brine (2×100 mL). The phases wereseparated. The organic phase was dried over MgSO₄ and concentrated invacuo. The crude mixture was purified over silica gel chromatography(EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as apale yellow liquid.

[0258]¹H NMR 2 (CDCl₃) δ ppm: 1.1 to 2.4 (m, 10H); 3.7 (s, 3H); 4.25(dd, 1H); 4.45 (dd, 1H).

[0259] MS ES⁺ [MW+1]⁺: 202.

[0260] Octahydro-isoindol-1-one (3)

[0261] A solution of 2 (5.42 g; 27 mmol) and nickel sponge catalyst(cat.) in methanol (100 mL) was stirred at 30° C. for 4 hours under ahydrogen atmosphere (70 psi). The catalyst was filtered off through acelite pad, and the filtrate was concentrated under vacuum.Recrystallization of the crude solid (ether/heptane) gave 3 (3.69 g;26.5 mmol; 98%) as a white powder.

[0262]¹H NMR (CDCl₃) δ ppm: 1.2 to 2.4 (m, 10H); 2.9 (d, 1H); 3.35 (m,1H); 5.7 (bs, 1H).

[0263] MS ES⁺ [MW+1]⁺: 140.

[0264] 1-Oxo-octahydro-isoindole-2-carboxylic acid tert-butyl ester (4)

[0265] To 3 (835 mg; 6 mmol) in suspension in tetrahydrofuran (7 mL) wassuccessively added, under an argon atmosphere, 4-dimethylaminopyridine(18.3 mg; 0.15 mmol), triethylamine (0.84 mL; 6 mmol) and BOC₂O (2.62 g;12 mmol). The reaction mixture was stirred at room temperature for 3days. The solvent was removed under vacuum. The residue was diluted withdiethyl ether (20 mL) and washed with water (2×10 mL). The phases wereseparated, and the organic phase was dried over MgSO₄ and concentrated.The crude oil was purified over silica gel chromatography (ether/heptane1:1) to give 4 (986 mg; 4.1 mmol; 70%) as a white solid.

[0266]¹H NMR (CDCl₃) δ ppm: 1.2 to 2.6 (m, 10H); 1.5 (s, 9H); 3.4 (d,1H); 3.6 (dd, 1H).

[0267] MS ES+ [MW+1]⁺: 240.

[0268][3aS-(3α7aα)]-7a-tert-Butoxycarbonylmethyl-1-oxo-octahydro-isoindole-2-carboxylicacid tert-butyl ester (5)

[0269] Lithium diisopropylamide was prepared by dropwise addition ofn-BuLi (1.39 mL; 2.5 M in hexanes; 3.47 mmol) to a stirred and cooled(−10° C.) solution of i-Pr₂NH (0.63 mL; 4.5 mmol) in dry tetrahydrofuran(33 mL). Stirring was continued for 20 minutes. The mixture was cooledto −78° C. and 4 (832 mg; 3.47 mmol), dissolved in dry tetrahydrofuran(2 mL), was added over 5 minutes. After a further 30 minutes,tert-Butylbromoacetate (0.77 mL; 5.21 mmol) was added dropwise. Themixture was then allowed to warm up to room temperature.N,N-Dimethylpropyleneurea (5 mL; 41.3 mmol) was added, and the reactionmixture was heated up to 75° C. for 5 hours. After cooling, saturatedNH₄Cl (10 mL) was added, and the mixture was extracted with diethylether (2×20 mL). The phases were separated, and the organic phase wasdried over MgSO₄ and concentrated. The residue was purified over silicagel chromatography (ether/heptane 1:1) to give 5 (840 mg; 2.37 mmol;70%) as a colorless oil.

[0270]¹H NMR (CDCl₃) δ ppm: 1.2 to 1.7 (m, 8H); 1.4 (s, 9H); 1.55 (s,9H); 2.5 (m, 1H); 2.55 [AB]q, 2H); 3.45 (dd, 1H); 3.75 (dd, 1H).

[0271] MS ES+ [MW+23]⁺: 376.

[0272][3aS-(α7aα)]-3a-tert-Butoxycarbonylmethyl-octahydro-isoindole-2-carboxylicacid tert-butyl ester (6)

[0273] To a cooled (−78° C.) solution of 5 (340 mg; 0.96 mmol) in drytetrahydrofuran (6 mL) was added, under an argon atmosphere, LiBHEt₃(1.15 mL; 1 M in THF; 1.15 mmol). The reaction mixture was quenchedafter 4 hours by addition of saturated aqueous NaHCO₃ (1.8 mL). Themixture was allowed to warm up to 0° C. Thirty percent H₂O₂ (5 drops)was added, and the mixture was stirred at 0° C. for a further 30minutes. The solvent was then removed under vacuum, and the aqueousphase was extracted with CH₂Cl₂ (3×5 mL). The organic phases werecombined, dried over MgSO₄, and concentrated. To the crude residue inCH₂Cl₂ (15 mL) was added, at −78° C., under an argon atmosphere, Et₃SiH(0.15 mL; 0.96 mmol) and BF₃ Et₂O (0.135 mL; 1.05 mmol). After stirringfor 30 minutes, a further Et₃SiH (0.15 mL; 0.96 mmol) and BF₃Et₂O (0.135mL; 1.05 mmol) were added, and the reaction mixture was stirred at −78°C. for 3 hours. Quenching was achieved at −78° C. by addition ofsaturated aqueous NaHCO₃ (1.5 mL). The phases were separated, and theorganic phase was dried over MgSO₄ and concentrated. The residue waspurified over silica gel chromatography (Et₂O/heptane 1:1) to give 6(157 mg; 0.46 mmol; 48%) as a colorless oil.

[0274]¹H NMR (CDCl₃) δ ppm: 1.2 to 1.4 (m, 26H); 2 (m, 1H); 2.15 (d,1H); 2.55 (dd, 1H); 3.2 to 3.5 (m, 4H).

[0275] MS ES+ [MW+1]⁺: 340.

[0276] [3aS-(3α7aα)]-(Octahydro-isoindol-3a-yl)-acetic acidtrifluoroacetate (7)

[0277] A solution of 6 (100 mg; 0.29 mmol) in a mixture CH₂Cl₂/TFA (2mL; 50:50) was stirred at room temperature for 2 hours. The solvent wasremoved under vacuum. The residue was diluted with water (2 mL) andwashed with ether (2×2 mL). The phases were separated, and the aqueousphase was concentrated under vacuum to give 7 (60 mg; 0.17 mmol; 69%) asa pale yellow gum.

[0278]¹H NMR (D₂O) δ ppm: 1.4 to 1.8 (m, 8H); 2.3 (m, 1H); 2.5 (d, 1H);2.95 (d, 1H); 3.35 to 3.95 (m, 4H).

[0279] MS ES+ [MW+1]⁺: 184.

[0280] C, H, N Calc. for C₁₀H₁₇NO₂.1.0C₂HF₃O₂.0.7H₂O: C, 46.51; H, 6.31;N, 4.52. Observed: C, 46.48; H, 5.98; N, 4.57.

[0281] The following compounds can also be prepared by the abovesynthetic methods:

[0282] 7-Methyl-2-aza-spiro[4.4]nonane-4-carboxylic acid;

[0283] 7,8-Dimethyl-2-aza-spiro[4.4]nonane4-carboxylic acid;

[0284] 7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[0285] 7,9-Dimethyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[0286] Spiro[bicyclo[3.3.1]nonane-9,3′-pyrrolidine]-4′-carboxylic acid;

[0287]Spiro[pyrrolidine-3,2′-tricyclo[3.3.1.1^(3,7)]decane]-4-carboxylic acid;

[0288] 3-Amino-6-methyl-spiro[3.5]nonane-1-carboxylic acid;

[0289] 3-Amino-6,8-dimethyl-spiro[3.5]nonane-1-carboxylic acid;

[0290] 4-Amino-7-methyl-spiro[4.5]decane-1-carboxylic acid;

[0291] 4-Amino-7,9-dimethyl-spiro[4.5]decane-1-carboxylic acid;

[0292] 3-Amino-6-methyl-spiro[3.4]otane-1-carboxylic acid;

[0293] 3-Amino-6,7-dimethyl-spiro[3.4]octane-1-carboxylic acid;

[0294] 4-Amino-7-methyl-spiro[4.4]nonane-1-carboxylic acid; and

[0295] 4-Amino-7,8-dimethyl-spiro[4.4]nonane-1-carboxylic acid.

[0296] In all of the above compounds, all stereocenters may be R or S.

[0297] For example:

1. A compound of formula

or a pharmaceutically acceptable salt thereof or a prodrug thereofwherein R₁ to R₁₀ are each independently selected from hydrogen or astraight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl; mis an integer of from 0 to 3; n is an integer of from 1 to 2; o is aninteger of from 0 to 3; p is an integer of from 1 to 2; q is an integerof from 0 to 2; r is an integer of from 1 to 2; s is an integer of from1 to 3; t is an integer of from 0 to 2; and u is an integer of from 0to
 1. 2. A compound according to claim 1 of Formula I.
 3. A compoundaccording to claim 1 of Formula I wherein R₁ to R₁₀ is hydrogen; m is offrom 0 to 3; and n is 1 or
 2. 4. A compound according to claim 1selected from: (±)-2-Aza-spiro[3.5]nonane-1-carboxylic acidhydrochloride; (±)-2-Aza-spiro[4.5]decane-4-carboxylic acidhydrochloride; (R)-2-Aza-spiro[4.5]decane-4-carboxylic acidhydrochloride; (S)-2-Aza-spiro[4.5]decane-4-carboxylic acidhydrochloride; and (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid.
 5. Acompound according to claim 1 of Formula II.
 6. A compound according toclaim 1 of Formula II wherein R₁ to R₁₀ is hydrogen, o is from 0 to 3;and p is 1 to
 2. 7. A compound according to claim 1 of Formula IIIwherein R₁ to R₁₀ is hydrogen, q is from 0 to 2; and r is 1 to
 2. 8. Acompound according to claim 1 of Formula III wherein:(±)-[3aS-(3α,7aα)]-(Octahydro-isoindol-3a-yl)-acetic acidtrifluoroacetate.
 9. A compound according to claim 1 and selected from:7-Methyl-2-aza-spiro[4.4]nonane-4-carboxylic acid;[4α,5β(R*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;[4α,5α(S*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;[4α,5α(R*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;[4α,5β(S*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;7,8-Dimethyl-2-aza-spiro[4.4]nonane-4-carboxylic acid;7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;7,9-Dimethyl-2-aza-spiro[4.5]decane-4-carboxylic acid;Spiro[bicyclo[3.3.1]nonane-9,3′-pyrrolidine]-4′-carboxylic acid;Spiro[pyrrolidine-3,2′-tricyclo[3.3.1.1^(3,7)]decane]-4-carboxylic acid;3-Amino-6-methyl-spiro[3.5]nonane-1-carboxylic acid;3-Amino-6,8-dimethyl-spiro[3.5]nonane-1-carboxylic acid;4-Amino-7-methyl-spiro[4.5]decane-1-carboxylic acid;4-Amino-7,9-dimethyl-spiro[4.5]decane-1-carboxylic acid;3-Amino-6-methyl-spiro[3.4]octane-1-carboxylic acid;3-Amino-6,7-dimethyl-spiro[3.4]octane-1-carboxylic acid;4-Amino-7-methyl-spiro[4.4]nonane-1-carboxylic acid; and4-Amino-7,8-dimethyl-spiro[4.4]nonane-1-carboxylic acid.
 10. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 1 and a pharmaceutically acceptablecarrier.
 11. A method for treating epilepsy comprising administering atherapeutically effective amount of a compound according to claim 1 to amammal in need of said treatment.
 12. A method for treating faintnessattacks, hypokinesia, and cranial disorders comprising administering atherapeutically effective amount of a compound according to claim 1 to amammal in need of said treatment.
 13. A method for treatingneurodegenerative disorders comprising administering a therapeuticallyeffective amount of a compound according to claim 1 to a mammal in needof said treatment.
 14. A method for treating depression comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 to a mammal in need of said treatment.
 15. A method fortreating anxiety comprising administering a therapeutically effectiveamount of a compound according to claim 1 to a mammal in need of saidtreatment.
 16. A method for treating panic comprising administering atherapeutically effective amount of a compound according to claim 1 to amammal in need of said treatment.
 17. A method for treating paincomprising administering a therapeutically effective amount of acompound according to claim 1 to a mammal in need of said treatment. 18.A method for treating neuropathological disorders comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 to a mammal in need of said treatment.
 19. A compoundselected from: 2-Benzyl-2-aza-spiro[4.5]decane-4,4-dicarboxylic aciddimethyl ester hydrochloride; 2-Aza-spiro[4.5]decane-4,4-dicarboxylicacid dimethyl ester hydrochloride;1-Benzyloxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic acid tert-butylester; 1-Hydroxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic acidtert-butyl ester; 2-Aza-spiro[3.5]nonane-1,2-dicarboxylic acid2-tert-butyl ester;[3aS-(3α7aα)]-7a-tert-Butoxycarbonylmethyl-1-oxo-octahydro-isoindole-2-carboxylicacid tert-butyl ester; and[3aS-(α7aα)]-3a-tert-Butoxycarbonylmethyl-octahydro-isoindole-2-carboxylicacid tert-butyl ester.